The present invention relates generally to the introduction of neuropharmaceutical agents into the brain by transcytosis across the blood-brain barrier. More particularly, the present invention relates to chimeric peptides which are capable of transporting neuropharmaceutical agents into the brain by receptor-mediated transcytosis across the blood-brain barrier.
The vertebrate brain has a unique capillary system which is unlike that in any other organ in the body. The unique capillary system has morphologic characteristics which make up the blood-brain barrier (BBB). The blood-brain barrier acts as a systemwide cellular membrane which separates the brain interstitial space from the blood.
The unique morphologic characteristics of the brain capillaries which make up the BBB are: (a) epithelial-like high resistance tight junctions which literally cement all endothelia of brain capillaries together, and (b) scanty pinocytosis or transendothelial channels, which are abundant in endothelia of peripheral organs. Due to the unique characteristics of the blood-brain barrier, hydrophilic drugs end peptides that readily gain access to other tissues in the body are barred from entry into the brain or their rates of entry are very low.
Various strategies have been developed for introducing those drugs into the brain which otherwise would not cross the blood-brain barrier. The most widely used strategies involve invasive procedures where the drug is delivered directly into the brain. The most common procedure is the implantation of a catheter into the ventricular system to bypass the blood-brain barrier and deliver the drug directly to the brain. These procedures have been used in the treatment of brain diseases which have a predilection for the meninges, e.g., leukemic involvement of the brain.
Although invasive procedures for the direct delivery of drugs to the brain ventricles have experienced some success, they have not been entirely successful because they only distribute the drug to superficial areas of the brain tissues, and not to the structures deep within the brain. Further, the invasive procedures are potentially harmful to the patient.
Other approaches to circumventing the blood-brain barrier utilize pharmacologic-based procedures involving drug latentiation or the conversion of hydrophilic drugs into lipid-soluble drugs. The majority of the latentiation approaches involve blocking the hydroxyl, carboxyl and primary amine groups on the drug to make it more lipid-soluble and therefore more easily transported across the blood-brain barrier. Although the pharmacologic approaches have been used with some success, they may not be entirely satisfactory for delivery of peptides through the BBB based on the inventor's experience with cyclosporin transport through the BBB. Cyclosporin is a highly latentiated (lipid-soluble) peptide that crosses the BBB relatively slowly.
Another approach to circumventing the blood-brain barrier involves the intra-arterial infusion of hypertonic substances which transiently open the blood-brain barrier to allow passage of hydrophilic drugs. However, hypertonic substances are potentially toxic and may damage the blood-brain barrier.
There presently is a need to provide improved substances and methods for delivering hydrophilic drugs and peptides across the blood-brain barrier and into the brain. I is desirable that such improved substances and methods provide for uniform introduction of the hydrophilic peptide or drug throughout the brain and present as little risk to the patient as possible.